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Prior testosterone replacement therapy may impact spermatogenic response to combined gonadotropin therapy in severe congenital hypogonadotropic hypogonadism
Ravikumar Shah · Virendra Patil · Vijaya Sarathi · Anurag R. Lila · Margaret Zacharin · Brijesh Krishnappa · Manjeetkaur Sehemby · Sanjeet Kumar Jaiswal · Pratap L. Jadhav · Swati Ramteke‑Jadhav · Nalini Shah · Tushar Bandgar
Abstract
Objective To study the effect of prior testosterone replacement therapy (TRT) on the spermatogenic response to combined gonadotropin therapy (CGT) in severe and partial phenotype congenital hypogonadotropic hypogonadism (CHH) patients.
Design Retrospective cohort study.
Setting Tertiary care center.
Patients Patients of CHH without (n=17) and with prior TRT (n=18) were subdivided into severe and partial groups, based on mean testicular volume≤3 cc and>3 cc respectively.
Intervention Participants were treated with hMG at a dose of 75–150 U 3/week and gradually escalating doses of hCG until maximum dose (2000 U 3/week or 5000 U 2/week) or serum total testosterone of≥3.5 ng/ml was reached.
Main outcome measures Final mean TV, trough serum testosterone (T), sperm concentration
Results Thirty-five patients (20 severe, baseline mean TV of 3.6±2.7 ml) were started on CGT at 24.8±6.1 years. The median duration of prior TRT was 38 (IQR 10–63.75) months in the exposed group. After 33±12 months, final mean TV was 8.9±5.5 ml, 86% achieved serum testosterone>3.5 ng/ml and 70% achieved spermatogenesis [median 5 (0–12.6) million/ml]. Patients without prior TRT had significantly higher peak sperm count than those with prior- TRT (median 9 vs 0.05 million/ml, p=0.004). This effect of prior TRT was more pronounced in severe phenotype patients (median 7 vs 0 million/ml, p=0.01).
Conclusion Prior-TRT may interfere with spermatogenic response to CGT in CHH patients, especially in those with a severe phenotype.
Introduction
Congenital isolated hypogonadotropic hypogonadism (CHH) in men is one of the few treatable causes of male infertility [1]. 75–80% of CHH patients achieve spermatogenesis, either with combined gonadotropin therapy (CGT) comprising of human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (rFSH)/human menopausal gonadotropin (hMG) or pulsatile gonadotropin-releasing hormone (GnRH) therapy [2]. The degree of spontaneous testicular development and cryptorchidism is well-known predictors of response [2]. Typically, partial phenotype [single testicular volume (STV)≥4 ml or bi-testicular volume (BTV)≥8 ml)] patients have earlier (~ 6 months vs ~ 18–24) and better spermatogenic response to CGT than those with the severe phenotype (STV <4 ml or BTV <8 ml) [1]. Poor spermatogenic response to CGT in the latter has been attributed to the absence of a mini-puberty and slender Sertoli cell pool to support future spermatogenesis [1]. Sequential therapy with FSH pre-treatment followed by CGT or GnRH [3, 4], and more recently, gonadotropin therapy during infancy to mimic mini-puberty have been proposed to improve the future fertility potential in such patients [5].
The role of prior testosterone replacement therapy (TRT) on the future spermatogenic response to CGT remains debatable [6]. Two previous studies from the same center have shown the detrimental effects of prior TRT [7, 8]. However, few studies, including a meta-analysis, have refuted a negative impact of prior TRT on spermatogenesis and fertility [2, 9–11]. The majority of studies reporting no effect of prior TRT on spermatogenic response to CGT have included hypogonadotropic hypogonadism (HH) patients of varied etiologies (pre-and post-pubertal onset). Also, the conclusion regarding the effect of prior TRT in the meta-analysis was limited by ecological fallacy (2). Importantly, two recent, larger studies found no interference from prior TRT; however, there were several potential confounders in these studies which might have affected the interpretations regarding the effect of prior TRT [11, 12].
In patients with partial phenotype, Sertoli cells would have had some exposure to mini-pubertal FSH with partial development prior to TRT. In contrast, patients with a severe phenotype have an immature testis with late fetal characteristics, due to lack of exposure to the perinatal FSH surge of mini-puberty. In the latter group, as demonstrated in histologic studies of primates, TRT may lead to early maturation of Sertoli cells suggesting a larger potential for the detrimental effect of prior TRT on the spermatogenic response to CGT in them [13]. Lack of phenotype-based subgroup analysis might have masked the effect of prior TRT in most of the previous studies reporting no detrimental effect of prior TRT. Hence, we have analyzed the spermatogenic response to CGT in a cohort of CHH patients, including a phenotype-based subgroup analysis.
*Combined gonadotropin therapy regimen included subcutaneous administration of highly purified urinary-derived hCG (FERTIGYN®, Sun Pharma, India) and hMG (GMHHP®, Sun Pharma, India) available as lyophilized ampoules with diluent via self-injection using an insulin syringe. All the patients were concurrently initiated on hMG and hCG. All the cases were started with hMG 75 units 3 ×/ week and dose escalation to 150 units 3×/week was done in cases with inadequate inhibin-B and/or spermatogenesis responses. The initial dose of hCG in patients without prior TRT was 500 U twice weekly and 1000–2000 U twice weekly in patients with prior TRT. The dose of hCG was titrated every three months based on the trough (72 hours after the last hCG injection) serum total testosterone levels to achieve and maintain a level of≥3.5 ng/ml, or till maximum hCG dose (2000 units thrice a week or 5000 units twice a week) was reached.
*Though gonadal toxicity with higher hCG doses has been shown in in-vitro and rat studies; this was not seen in our few cases treated with higher hCG doses (10,000 units/week) [20, 21].
Conclusion and study implication
Prior TRT may negatively affect the spermatogenic response to CGT in CHH patients with a severe phenotype. Hence, the use of gonadotropins, rather than androgens, may be preferred for pubertal induction in them. Larger studies including exclusive CHH patients with severe phenotype are warranted
Ravikumar Shah · Virendra Patil · Vijaya Sarathi · Anurag R. Lila · Margaret Zacharin · Brijesh Krishnappa · Manjeetkaur Sehemby · Sanjeet Kumar Jaiswal · Pratap L. Jadhav · Swati Ramteke‑Jadhav · Nalini Shah · Tushar Bandgar
Abstract
Objective To study the effect of prior testosterone replacement therapy (TRT) on the spermatogenic response to combined gonadotropin therapy (CGT) in severe and partial phenotype congenital hypogonadotropic hypogonadism (CHH) patients.
Design Retrospective cohort study.
Setting Tertiary care center.
Patients Patients of CHH without (n=17) and with prior TRT (n=18) were subdivided into severe and partial groups, based on mean testicular volume≤3 cc and>3 cc respectively.
Intervention Participants were treated with hMG at a dose of 75–150 U 3/week and gradually escalating doses of hCG until maximum dose (2000 U 3/week or 5000 U 2/week) or serum total testosterone of≥3.5 ng/ml was reached.
Main outcome measures Final mean TV, trough serum testosterone (T), sperm concentration
Results Thirty-five patients (20 severe, baseline mean TV of 3.6±2.7 ml) were started on CGT at 24.8±6.1 years. The median duration of prior TRT was 38 (IQR 10–63.75) months in the exposed group. After 33±12 months, final mean TV was 8.9±5.5 ml, 86% achieved serum testosterone>3.5 ng/ml and 70% achieved spermatogenesis [median 5 (0–12.6) million/ml]. Patients without prior TRT had significantly higher peak sperm count than those with prior- TRT (median 9 vs 0.05 million/ml, p=0.004). This effect of prior TRT was more pronounced in severe phenotype patients (median 7 vs 0 million/ml, p=0.01).
Conclusion Prior-TRT may interfere with spermatogenic response to CGT in CHH patients, especially in those with a severe phenotype.
Introduction
Congenital isolated hypogonadotropic hypogonadism (CHH) in men is one of the few treatable causes of male infertility [1]. 75–80% of CHH patients achieve spermatogenesis, either with combined gonadotropin therapy (CGT) comprising of human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (rFSH)/human menopausal gonadotropin (hMG) or pulsatile gonadotropin-releasing hormone (GnRH) therapy [2]. The degree of spontaneous testicular development and cryptorchidism is well-known predictors of response [2]. Typically, partial phenotype [single testicular volume (STV)≥4 ml or bi-testicular volume (BTV)≥8 ml)] patients have earlier (~ 6 months vs ~ 18–24) and better spermatogenic response to CGT than those with the severe phenotype (STV <4 ml or BTV <8 ml) [1]. Poor spermatogenic response to CGT in the latter has been attributed to the absence of a mini-puberty and slender Sertoli cell pool to support future spermatogenesis [1]. Sequential therapy with FSH pre-treatment followed by CGT or GnRH [3, 4], and more recently, gonadotropin therapy during infancy to mimic mini-puberty have been proposed to improve the future fertility potential in such patients [5].
The role of prior testosterone replacement therapy (TRT) on the future spermatogenic response to CGT remains debatable [6]. Two previous studies from the same center have shown the detrimental effects of prior TRT [7, 8]. However, few studies, including a meta-analysis, have refuted a negative impact of prior TRT on spermatogenesis and fertility [2, 9–11]. The majority of studies reporting no effect of prior TRT on spermatogenic response to CGT have included hypogonadotropic hypogonadism (HH) patients of varied etiologies (pre-and post-pubertal onset). Also, the conclusion regarding the effect of prior TRT in the meta-analysis was limited by ecological fallacy (2). Importantly, two recent, larger studies found no interference from prior TRT; however, there were several potential confounders in these studies which might have affected the interpretations regarding the effect of prior TRT [11, 12].
In patients with partial phenotype, Sertoli cells would have had some exposure to mini-pubertal FSH with partial development prior to TRT. In contrast, patients with a severe phenotype have an immature testis with late fetal characteristics, due to lack of exposure to the perinatal FSH surge of mini-puberty. In the latter group, as demonstrated in histologic studies of primates, TRT may lead to early maturation of Sertoli cells suggesting a larger potential for the detrimental effect of prior TRT on the spermatogenic response to CGT in them [13]. Lack of phenotype-based subgroup analysis might have masked the effect of prior TRT in most of the previous studies reporting no detrimental effect of prior TRT. Hence, we have analyzed the spermatogenic response to CGT in a cohort of CHH patients, including a phenotype-based subgroup analysis.
*Combined gonadotropin therapy regimen included subcutaneous administration of highly purified urinary-derived hCG (FERTIGYN®, Sun Pharma, India) and hMG (GMHHP®, Sun Pharma, India) available as lyophilized ampoules with diluent via self-injection using an insulin syringe. All the patients were concurrently initiated on hMG and hCG. All the cases were started with hMG 75 units 3 ×/ week and dose escalation to 150 units 3×/week was done in cases with inadequate inhibin-B and/or spermatogenesis responses. The initial dose of hCG in patients without prior TRT was 500 U twice weekly and 1000–2000 U twice weekly in patients with prior TRT. The dose of hCG was titrated every three months based on the trough (72 hours after the last hCG injection) serum total testosterone levels to achieve and maintain a level of≥3.5 ng/ml, or till maximum hCG dose (2000 units thrice a week or 5000 units twice a week) was reached.
*Though gonadal toxicity with higher hCG doses has been shown in in-vitro and rat studies; this was not seen in our few cases treated with higher hCG doses (10,000 units/week) [20, 21].
Conclusion and study implication
Prior TRT may negatively affect the spermatogenic response to CGT in CHH patients with a severe phenotype. Hence, the use of gonadotropins, rather than androgens, may be preferred for pubertal induction in them. Larger studies including exclusive CHH patients with severe phenotype are warranted
